| Renal ischemia/reperfusion (I/R) and endotoxemia are the major sequential or concurrent clinical insults resulting in acute renal failure (ARF). Although both conditions may involve necrosis or apoptotis induction by oxygen free radical formation and neutrophil sequestration/activation, cause-effect relations are not clear, and - in fact - might differ substantially among the conditions. In addition, the final downstream signaling events leading to, potentially preventable or reversible, apoptosis in these conditions have not yet been resolved. The main research objectives of this proposal, therefore, are i) to establish the susceptibility for I/R damage (apoptosis vs. necrosis) of the different morphological and functional units (i.e. vessels, glomeruli and tubuli) in the kidney; ii) to investigate the effects of inflammation, i.e. endotoxin exposure; iii) to determine the contribution and relative importance of the signal transduction routes involved in apoptosis induction in the conditions; and iv) to investigate the effects on of specific caspase inhibitors on apoptosis induction pathways. To reach these goals we will use - among other things - the newly implemented 3D live-cell digital imaging microscope (3D-DIM) facility. It concerns in vitro studies of signaling molecules in isolated vessels as well as in cultures of glomerular mesangial and tubular cells. This may be the first step in enhancing our understanding of the intracellular mechanisms provoking ARF. |
